Systems biology analysis of human genomes points to key pathways conferring spina bifida risk.

Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.

Joubert syndrome labeled as hypotonic cerebral palsy.

Joubert syndrome (JS) is a rare autosomal recessive disorder with cerebellar vermis hypoplasia and complex brainstem malformation. The diagnosis of cases can be difficult as the presentation can be similar to cases of cerebral palsy. We present a case of JS in an 18-month-old girl who presented to pediatric rehabilitation with a diagnosis of hypotonic cerebral palsy and abnormal eye movements. The brain MRI confirmed the typical brain malformations.

Long-term outcomes of pneumococcal meningitis in childhood and adolescence.

A vaccine to prevent pneumococcal meningitis (PM) has recently been introduced. However, contemporary data to inform cost-effectiveness analysis and justify its routine use are sparse. We examined the cognitive, educational, psychological and social outcomes of PM in childhood. We completed a population-based case-control study in two regions of the UK. Children and young people currently between 3 and 20 years of age that had been diagnosed with PM ≤14 years of age were identified from active regional surveillance. Controls were siblings or neighbours of similar age. Standardised questionnaires and neuropsychological testing was administered to assess IQ, educational attainments, memory, psychological distress, quality of life and hearing impairment. Data were available on 97 patients and 93 controls. Eighty-four patients had a sibling/neighbour-matched control. Both matched and unmatched analyses were completed, and results of the 84 matched comparisons were highly similar to the unmatched. For the total sample, controls were similar in age, ethnicity and socioeconomic status. Median age at meningitis was 11 months. Median time between meningitis and assessment was 6.0 years. In the matched analysis, partial or profound hearing impairment was reported in 14% of patients and 1% of controls. Patients had significantly lower mean full-scale IQ (p = 0.05), verbal IQ (p = 0.0008), numeracy (p = 0.02), total quality of life (p = 0.04), school functioning (p = 0.005), psychosocial functioning (p = 0.001) and psychological difficulties (p = 0.01). Parents of patients reported greater functional disability (p = 0.008), impairment in all aspects of quality of life (p = 0.001) and psychological difficulties (p < 0.0006). Findings for IQ were not materially different when analyses were repeated only in those without hearing impairment. In multivariate regression analysis that included both case-control status and hearing status, both being a patient (p = 0.001) and having profound hearing impairment (p = 0.001) were independently associated with lower full-scale IQ. Conclusions Pneumococcal meningitis is associated with major sequelae. Our findings strongly support the introduction of pneumococcal conjugate vaccine as part of routine childhood vaccination programmes internationally.

Analgesia and sedation modalities used with botulinum toxin injections in children with cerebral palsy: a literature review.

Cerebral palsy (CP) is a non-progressive motor dysfunction leading to multiple morbidities, including spasticity, which can be managed with botulinum toxin injection (BTI). This literature review aims to examine published studies on the efficacy and safety of different interventions used to reduce pain and anxiety associated with BTI in children with CP. A literature review of all published evidence in English language, or with an English translation between 1999 and 2019, using PubMed, EBSCO host, and Medline databases was carried out. All identified papers were screened for inclusion criteria. Data from included papers were entered and analyzed on an Excel database. Twenty-one studies conducted in multiple clinical settings identified 10 different analgesia and sedation modalities including intravenous ketamine, midazolam, inhaled nitrous oxide, general anesthesia, and Eutectic Mixture of Local Anesthetics (EMLA®) cream. Most of the studies were descriptive with the exception of two clinical trials and one qualitative study. All interventions had some adverse effects, but they were generally mild and no long-term sequelae were reported. The combination of inhaled nitrous oxide with EMLA® cream showed promising primary results. However, ketamine and midazolam combination could be a safe alternative. Currently, there is no sufficient data to draw on the superiority of any modality. Further high-quality studies are warranted.

Facemask against viral respiratory infections among Hajj pilgrims: A challenging cluster-randomized trial.

BACKGROUND: In this large-scale cluster-randomized controlled trial (cRCT) we sought to assess the effectiveness of facemasks against viral respiratory infections. METHODS AND RESULTS: Over three consecutive Hajj seasons (2013, 2014, 2015) pilgrims' tents in Makkah were allocated to 'facemask' or 'no facemask' group. Fifty facemasks were offered to participants in intervention tents, to be worn over four days, and none were offered to participants in control tents. All participants recorded facemask use and respiratory symptoms in health diaries. Nasal swabs were collected from the symptomatic for virus detection by reverse transcription polymerase chain reaction. Clinical symptoms and laboratory results were analyzed by 'intention- to-treat' and 'per-protocol'. A total of 7687 adult participants from 318 tents were randomized: 3864 from 149 tents to the intervention group, and 3823 from 169 tents to the control group. Participants were aged 18 to 95 (median 34, mean 37) years, with a male to female ratio of 1:1.2. Overall, respiratory viruses were detected in 277 of 650 (43%) nasal/pharyngeal swabs collected from symptomatic pilgrims. Common viruses were rhinovirus (35.1%), influenza (4.5%) and parainfluenza (1.7%). In the intervention arm, respectively 954 (24.7%) and 1842 (47.7%) participants used facemasks daily and intermittently, while in the control arm, respectively 546 (14.3%) and 1334 (34.9%) used facemasks daily and intermittently. By intention-to-treat analysis, facemask use did not seem to be effective against laboratory-confirmed viral respiratory infections (odds ratio [OR], 1.4; 95% confidence interval [CI], 0.9 to 2.1, p = 0.18) nor against clinical respiratory infection (OR, 1.1; 95% CI, 0.9 to 1.4, p = 0.40). Similarly, in a per-protocol analysis, facemask use did not seem to be effective against laboratory-confirmed viral respiratory infections (OR 1.2, 95% CI 0.9-1.7, p = 0.26) nor against clinical respiratory infection (OR 1.3, 95% CI 1.0-1.8, p = 0.06). CONCLUSION: This trial was unable to provide conclusive evidence on facemask efficacy against viral respiratory infections most likely due to poor adherence to protocol.

Health related quality of life in survivors of pneumococcal meningitis.

AIM: To estimate the overall long-term health related quality of life implications of an episode of pneumococcal meningitis in childhood. METHOD: Cases were identified through two regional UK surveillance studies and traced via their general practitioners (GPs) or local hospital paediatrician. Siblings were used as controls where available. Health related quality of life was assessed using the health utilities index (HUI). Mean utility scores were compared between cases and controls and univariate linear regression was used to identify factors that influenced the overall utility scores. RESULTS: HUI data were available for 71 cases and 66 controls. The mean overall utility score for cases 0.774 (95% CI 0.711- 0.837) was significantly lower than for controls 0.866 (95% CI 0.824-0.907) (p-value = 0.0185). Hearing was the most significantly affected health attribute (p-value < 0.006). In cases, males had lower quality of life scores than females (p-value = 0.018), however this was not seen in controls. CONCLUSION: An episode of pneumococcal meningitis results in a long-term decrement in overall health related quality of life and is significantly related to hearing loss.

Value of rapid testing for influenza among Hajj pilgrims.

BACKGROUND: Muslim pilgrims going on the Hajj are at risk of influenza. The treatment and prevention of influenza with antiviral drugs depends on rapid diagnosis using a near-patient test such as the QuickVue influenza test. The suitability of this test among pilgrims has not been studied in the past and this study assesses the usefulness of the test for diagnosing influenza among those attending the Hajj. METHODS: The sensitivity and specificity of the QuickVue test were measured against reverse transcriptase polymerase chain reaction by undertaking the tests on nasal swab samples from pilgrims. RESULTS: The sensitivity and specificity of the QuickVue test were 22% and 99%, respectively, and its likelihood ratio for a positive and a negative test were 22 and 0.79 in that order. CONCLUSION: The QuickVue influenza test using nasal swabs is poorly sensitive for diagnosing influenza among Hajj pilgrims. Given its high specificity and an even higher likelihood ratio for a positive test it may still be a very useful tool for influenza surveillance at the Hajj.

Impact of meningitis on intelligence and development: A systematic review and meta-analysis.

BACKGROUND: We undertook a systematic review and meta-analysis to address the question "what is the impact of meningitis on IQ and development." METHODS: Search: conducted using standardized search terms across Medline, PsychInfo and EMBASE to 06/2014. Eligibility: human studies of any infectious aetiology of meningitis reporting IQ or infant developmental age or stage outcomes. Quality: Centre for Evidence Based Medicine, Oxford, quality tools. Analysis: random effects meta-analysis by organism. RESULTS: 39 studies were included in the review, 34 providing data on IQ (2015 subjects) and 12 on developmental delay (382 subjects). Across all bacterial organisms, meningitis survivors had a mean IQ 5.50 (95% CI: -7.19, -3.80; I2 = 47%, p = 0.02) points lower than controls. IQ was significantly lower than controls for Neisseria meningitides (NM: 5 points) and Haemophilus influenzae b (Hib: 6 points) but not in viral meningitis, with only single studies included for Streptococcus pneumoniae (SP) and group B streptococcus (GBS). The pooled relative risk (RR) for low IQ (IQ<70) in survivors of bacterial meningitis compared with controls was 4.99 (95% CI: 3.17, 7.86) with no significant heterogeneity (I2 = 49%, p = 0.07). Developmental delay of approximately 0.5SD was reported in studies of bacterial meningitis but no delay in the only study of viral meningitis. CONCLUSIONS: We found moderate evidence that surviving bacterial meningitis has a deleterious impact on IQ and development but no evidence that viral meningitis had meaningful cognitive impacts. Survivors of bacterial meningitis should be routinely offered screening for cognitive deficits and developmental delay in addition to hearing loss.

National hospital data for intussusception: Data linkage and retrospective analysis to assess quality and use in vaccine safety surveillance.

OBJECTIVES: To assess the quality of national Hospital Episode Statistics (HES) data for intussusception, and evaluate this routinely collected database for rotavirus vaccine safety surveillance by estimating pre-vaccination trends in intussusception hospitalisation. METHODS: Data linkage was performed between HES and prospective intussusception data from the British Paediatric Surveillance Unit (BPSU), followed by capture-recapture analysis to verify HES data quality. Inclusion criteria were infants aged less than 12 months and admitted for intussusception to National Health Service (NHS) hospitals in England from March 2008 to March 2009. To estimate pre-vaccination incidence rates of intussusception, we performed a retrospective analysis of HES data. Infants aged less than 12 months and admitted for intussusception to NHS hospitals in England between 1995 and 2009 were included. RESULTS: Data linkage between 254 cases of intussusception identified in HES data and 190 cases reported via the BPSU resulted in 163 cases common to both data sources. Of remaining 91 cases in HES, 37 had confirmed intussusception. HES data accuracy was 78.7% (200 confirmed/254 cases) and completeness for intussusception was 86% (163 matched/190 BPSU cases) compared to 81.5% (163 matched/200 HES cases) for BPSU. A total of 233 (95% CI: 227.4 to 238.8) intussusception cases were estimated for the infant population (2008 to 2009). For retrospective analysis, of 6462 intussusception admissions in HES data (1995 to 2009), 1594 (24.7%) were duplicate admissions. A declining trend in intussusception incidence was observed in the infant population, from 86/100,000 in 1997 to 34/100,000 in 2009 (60% reduction, P<0.001). Cosinor modelling showed an excess of cases among infants in winter and spring (P<0.001, n=4957, 1995 to 2009). CONCLUSION: National hospital data capture the majority of admissions for intussusception and should be considered for the post-implementation surveillance of rotavirus vaccine safety in England.

Changes in laboratory features of 192 children with imported falciparum malaria treated with quinine.

Little is known about changes in laboratory values of children with imported falciparum malaria. Of 192 children, 69% had parasitemia of 2% or less and 64% had platelets <150 x 10/L. In 20%, parasite counts rose within 12-24 hours of starting treatment before falling, whereas the platelet counts dropped in 45% but returned to normal levels within 5 days. Hemoglobin values were <10 g/dL in 31% at presentation and dropped in 61% at 5-21 days after treatment, but did not fall below 6.8 g/dL in any case. Blood cultures were negative in all children. Hyponatremia (n = 16), jaundice (n = 4) and hypoglycemia (n = 0) were uncommon. Thus most children presented with abnormal laboratory values, which initially worsened in a significant proportion, but none required active intervention once therapy was initiated.

Neurodevelopmental and Cognitive Outcomes of Classical Homocystinuria: Experience from Qatar.

BACKGROUND: Classical homocystinuria due to cystathionine ß-synthase (CBS) deficiency (OMIM 236200) is a recessively inherited condition caused by mutations in the CBS gene. The founder mutation p.R336C accounts for almost all CBS deficiency in Qatar, affecting approximately 1 in 1,800 births, making it the most prevalent monogenic disease among the Qatari population. Untreated patients can have severe intellectual disability (ID), devastating multisystem complications and premature death. Current treatment is based on pharmacology therapy and life-long methionine-restricted diet, which is difficult to maintain particularly in late diagnosed individuals. Data on the neurodevelopmental and psychological impact of the disease on outcomes among Qatari patients are generally lacking and have not been studied. OBJECTIVES: To examine the cognitive, educational and psychological outcomes of classical homocystinuria on Qatari patients. SUBJECTS AND METHODS: Thirty-two cases with classical homocystinuria and 25 sibling controls were recruited to evaluate the neurodevelopmental and cognitive outcomes. We reviewed the subjects' medical record and collected pertinent clinical and educational data from parents. Stanford-Binet Intelligence Test (Arabic translation - 4th ed.) was used for cognitive (IQ) testing. RESULTS: The mean age for the subjects was 11.2 years (range 0.6-29) with 56% males. The majority of cases (93%) carried the mutation (p.R336C), and parental consanguinity was 84%. There were no differences between the two groups in the fine motor, expressive language, behavioural and visual skills. However, cases have much lower total IQ particularly in the domains of short memory, quantitative reasoning and visual-spatial domains. A significant number of adolescents and adult cases had medical co-morbidities as well as behavioural and emotional problems. CONCLUSION: Individuals with classical homocystinuria have many developmental and cognitive difficulties with significant number of cases having learning disability and lower IQs (cf. sibling controls) with adolescents and adults more affected. Those diagnosed by newborn screening have better developmental and cognitive outcomes compared to late diagnosed cases. Psychological and psychiatric referrals should be part of the standard of care for those cases.

Changes in the prevalence of influenza-like illness and influenza vaccine uptake among Hajj pilgrims: A 10-year retrospective analysis of data.

BACKGROUND: Influenza is an important health hazard among Hajj pilgrims. For the last ten years, pilgrims are being recommended to take influenza vaccine before attending Hajj. Vaccination coverage has increased in recent years, but whether there has been any change in the prevalence of influenza-like illness (ILI) is not known. In this analysis, we examined the changes in the rate of ILI against seasonal influenza vaccine uptake among Hajj pilgrims over the last decade. METHOD: Data for this analysis is a synthesis of raw and published data from eleven Hajj seasons between 2005 and 214. For seven Hajj seasons the data were obtained from studies involving pilgrims of UK, Saudi Arabia and Australia; and for the remaining four Hajj seasons data were abstracted from published studies involving pilgrims from multiple countries. The data from both sources were synthesised to estimate the relative risk (RR) of acquisition of ILI in vaccinated versus unvaccinated pilgrims. RESULTS: The pooled sample size of the included studies was 33,213 with most pilgrims being in the age band of 40-60 years (range: 0.5 to 95 years) and a male to female ratio of 1.6. The pilgrims originated, in order of frequency, from Iran, Australia, France, UK, Saudi Arabia, Indonesia, India, Algeria, Ivory Coast, Nigeria, Somalia, Turkey, Syria, Sierra Leone and USA. Except for one year (2008), data from individual years did not demonstrate a noticeable change in the rate of ILI against influenza vaccine coverage, however the combined data from all studies suggest that the prevalence of ILI decreased among Hajj pilgrims as the vaccine coverage increased over the last decade (RR 0.2, P<0.01). CONCLUSION: This analysis suggests that influenza vaccine might be beneficial for Hajj pilgrims. However, controlled trials aided by molecular diagnostic tools could confirm whether such an effect is real or ostensible.

A cluster-randomised controlled trial to test the efficacy of facemasks in preventing respiratory viral infection among Hajj pilgrims.

BACKGROUND: Cost-effective interventions are needed to control the transmission of viral respiratory tract infections (RTIs) in mass gatherings. Facemasks are a promising preventive measure, however, previous studies on the efficacy of facemasks have been inconclusive. This study proposes a large-scale facemask trial during the Hajj pilgrimage in Saudi Arabia and presents this protocol to illustrate its feasibility and to promote both collaboration with other research groups and additional relevant studies. METHODS/DESIGN: A cluster-randomised controlled trial is being conducted to test the efficacy of standard facemasks in preventing symptomatic and proven viral RTIs among pilgrims during the Hajj season in Mina, Mecca, Saudi Arabia. The trial will compare the 'supervised use of facemasks' versus 'standard measures' among pilgrims over several Hajj seasons. Cluster-randomisation will be done by accommodation tents with a 1:1 ratio. For the intervention tents, free facemasks will be provided to be worn consistently for 7days. Data on flu-like symptoms and mask use will be recorded in diaries. Nasal samples will be collected from symptomatic recruits and tested for nucleic acid of respiratory viruses. Data obtained from questionnaires, diaries and laboratory tests will be analysed to examine whether mask use significantly reduces the frequency of laboratory-confirmed respiratory viral infection and syndromic RTI as primary outcomes. CONCLUSIONS: This trial will provide valuable evidence on the efficacy of standard facemask use in preventing viral respiratory tract infections at mass gatherings. This study is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: ACTRN12613001018707 (http://www.anzctr.org.au).

W135 meningococcal pericarditis: report of two cases and review of the literature.

Pericarditis is a rare but recognized complication of meningococcal disease. After the 2000 and 2001 hajj in Saudi Arabia, a worldwide outbreak of meningococcal W135:2a:P1.2,5 (epidemic strain) was reported including the United Kingdom. Cases of meningococcal disease occurred in pilgrims and their household contacts; and community spread occurred among non-Muslims. Between July 2001 and January 2002, 2 children with pericarditis associated with W135 meningococcal disease were admitted to our hospital in east London.

Pericarditis after meningococcal infection: case report of a child with two distinct episodes.

Pericarditis is a recognized consequence of meningococcal disease. The incidence among all age groups is 3 to 19%. Repeated episodes of pericarditis after meningococcal disease have been reported previously in two adults but not in children. We describe the clinical and laboratory features of a child with two distinct episodes of pericarditis after Neisseria meningitidis serogroup C infection.

Meningococcal W135 carriage; enhanced surveillance amongst east London Muslim pilgrims and their household contacts before and after attending the 2002 Hajj.

BACKGROUND: For two successive years, 2000 and 2001, there was a world-wide outbreak of W135 meningococcal disease amongst pilgrims who attended the Hajj and in their contacts after returning home. METHODS: Beginning January 2002, we offered meningococcal quadrivalent polysaccharide vaccine (against serogroups A, C, Y and W135) to pilgrims and collected a throat swab for meningococcal W135 carriage before and after their pilgrimage. RESULTS: The overall Neisseria meningitidis carriage pre-Hajj was 8.3% and 6.3% post-Hajj. We found W135 carriage rates of 0.8% before and 0.6% after Hajj, respectively. 21% (36/174) of the pilgrims were treated with antibiotics for respiratory illness. CONCLUSION: The carriage of meningococcus W135 among UK pilgrims who visited the Hajj in 2002 was low. This contrasts with another study suggesting pilgrims frequently acquired N. meningitidis W135 carriage during 2001 Hajj. The use of the quadrivalent vaccine may account for this difference.

Viral respiratory infections among Hajj pilgrims in 2013.

Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged in the Arabian Gulf region, with its epicentre in Saudi Arabia, the host of the 'Hajj' which is the world's the largest mass gathering. Transmission of MERS-CoV at such an event could lead to its rapid worldwide dissemination. Therefore, we studied the frequency of viruses causing influenza-like illnesses (ILI) among participants in a randomised controlled trial at the Hajj 2013. We recruited 1038 pilgrims from Saudi Arabia, Australia and Qatar during the first day of Hajj and followed them closely for four days. A nasal swab was collected from each pilgrim who developed ILI. Respiratory viruses were detected using multiplex RT-PCR. ILI occurred in 112/1038 (11%) pilgrims. Their mean age was 35 years, 49 (44%) were male and 35 (31%) had received the influenza vaccine pre-Hajj. Forty two (38%) pilgrims had laboratory-confirmed viral infections; 28 (25%) rhinovirus, 5 (4%) influenza A, 2 (2%) adenovirus, 2 (2%) human coronavirus OC43/229E, 2 (2%) parainfluenza virus 3, 1 (1%) parainfluenza virus 1, and 2 (2%) dual infections. No MERS-CoV was detected in any sample. Rhinovirus was the commonest cause of ILI among Hajj pilgrims in 2013. Infection control and appropriate vaccination are necessary to prevent transmission of respiratory viruses at Hajj and other mass gatherings.